Targeting primary and metastatic uveal melanoma with a G protein inhibitor

Michael D. Onken; Carol M. Makepeace; Kevin M. Kaltenbronn; Joelle Choi; Leonel Hernandez-Aya; Katherine N. Weilbaecher; Kisha D. Piggott; P. Kumar Rao; Carla M. Yuede; Alethia J. Dixon; Patrick Osei-Owusu; John A. Cooper; Kendall J. Blumer

doi:10.1016/j.jbc.2021.100403

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Targeting primary and metastatic uveal melanoma with a G protein inhibitor

Journal article

Open access

Peer reviewed

Targeting primary and metastatic uveal melanoma with a G protein inhibitor

Michael D. Onken, Carol M. Makepeace, Kevin M. Kaltenbronn, Joelle Choi, Leonel Hernandez-Aya, Katherine N. Weilbaecher, Kisha D. Piggott, P. Kumar Rao, Carla M. Yuede, Alethia J. Dixon, …

The Journal of biological chemistry, Vol.296, 100403

Jan 2021

DOI: https://doi.org/10.1016/j.jbc.2021.100403

PMID: 33577798

Featured in Collection : UN Sustainable Development Goals @ Drexel

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Abstract

anticancer drug

drug action

eye

G protein inhibitor

G proteins/heterotrimeric

melanoma

uveal melanoma

Uveal melanoma (UM) is the most common intraocular tumor in adults. Nearly half of UM patients develop metastatic disease and often succumb within months because effective therapy is lacking. A novel therapeutic approach has been suggested by the discovery that UM cell lines driven by mutant constitutively active Gq or G11 can be targeted by FR900359 (FR) or YM-254890, which are bioavailable, selective inhibitors of the Gq/11/14 subfamily of heterotrimeric G proteins. Here, we have addressed the therapeutic potential of FR for UM. We found that FR inhibited all oncogenic Gq/11 mutants reported in UM. FR arrested growth of all Gq/11-driven UM cell lines tested, but induced apoptosis only in a few. Similarly, FR inhibited growth of, but did not efficiently kill, UM tumor cells from biopsies of primary or metastatic tumors. FR evoked melanocytic redifferentiation of UM tumor cells with low (class 1), but not high (class 2), metastatic potential. FR administered systemically below its LD50 strongly inhibited growth of PDX-derived class 1 and class 2 UM tumors in mouse xenograft models and reduced blood pressure transiently. FR did not regress xenografted UM tumors or significantly affect heart rate, liver function, hematopoiesis, or behavior. These results indicated the existence of a therapeutic window in which FR can be explored for treating UM and potentially other diseases caused by constitutively active Gq/11.

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Title: Targeting primary and metastatic uveal melanoma with a G protein inhibitor
Creators: Michael D. Onken - Washington University in St. Louis
Carol M. Makepeace - Washington University in St. Louis
Kevin M. Kaltenbronn - Washington University in St. Louis
Joelle Choi - Washington University in St. Louis
Leonel Hernandez-Aya - Washington University in St. Louis
Katherine N. Weilbaecher - Washington University in St. Louis
Kisha D. Piggott - Visual Sciences
P. Kumar Rao - Visual Sciences
Carla M. Yuede - Washington University in St. Louis
Alethia J. Dixon - Drexel University
Patrick Osei-Owusu - Drexel University
John A. Cooper - Washington University in St. Louis
Kendall J. Blumer - Washington University in St. Louis
Publication Details: The Journal of biological chemistry, Vol.296, 100403
Publisher: Elsevier
Resource Type: Journal article
Language: English
Academic Unit: Pharmacology and Physiology
Identifiers: 991019167898204721

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Collaboration types: Domestic collaboration
Web of Science research areas: Biochemistry & Molecular Biology